Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - 2020 - Rekeland, Mella, Fluge et al

"At baseline, only two of the responders had part-time work participation. During follow-up, at least nine out of 22 responders returned to either part-time of full-time work or studies."

Finally some objective outcomes This looks very promising, I think its very hard to start work or studies with ME without actually being better.

 

Despite the negative Rituximab trial, I think we should not discount the possibility that ME is an (auto)immune condition. This study and the fact that many people report temporary remissions during a cold / flu infection further support that idea.

Finally, other previously unexplained diseases have recently been found out to be auto-immune as well, for example Narcolepsy. Maybe the same story could be true for ME/CFS.

 

"Ten of the 12 patients (83.3%) positive for HLA alleles DQB1*03:03 and/or C*07:04 had a response, compared to 12 out of 28 patients (42.9%) negative for these HLA alleles (OR = 6.67; p = 0.028; Figure 6)"

Small sample size, but pretty interesting finding no?

 

Why would having a remission during cold/flu infection, point towards it being an autoimmune condition?

(I actually get the opposite - definite and severe worsening after a flu or cold).

 

"Also of note, three of the patients who registered relapse at 3–4 years still reported a 2-fold increase of their percent function levels as compared to baseline."

I find this fascinating. Suggests to me that ME-worsenings can be caused some coordinated immune dysfunction, and that disrupting it can lead to improved function. Its also good to know that the disease mechanism is not a permanent entity for everyone

 

Because an infection might divert the immune system from attacking the body to attacking the virus.

 

"Although the double blinded RituxME trial showed no significant differences between the rituximab and placebo groups for the outcome measures (35), there may still be a subgroup of ME/CFS patients that have an autoantibody-mediated disease where only few patients have autoantibody-production from early CD20-positive plasmablasts that can be targeted by rituximab. Other patients may still have autoantibody production, but from long-lived CD20-negative plasma cells. This mechanism is active in several rituximab refractory autoimmune diseases and could be compatible both with the total experience from our rituximab trials, and with the data from the present cyclophosphamide trial. Cytotoxic chemotherapy, such as cyclophosphamide, may inhibit B-cell activation and proliferation to new antibody-secreting cells, thus reducing the short-lived plasma cell compartment and recruitment of mature plasma cells"

Yes this is something we discussed on the old forum in the rituximab days. If we could find out if long lived plasma cells are a driving disease mechanism in ME we would quickly be a lot closer to finding treatments

 

I don’t think that the body stops attacking itself, because it’s attacking the virus. I actually thought those with autoimmune conditions can get worse with infections, either due to the condition itself or immunosuppression caused by medications. When I followed the lupus U.K. charity, they would post about people with lupus who died after catching infections and the importance of getting medical treatment.

This seems to be backed up by this, which is about opportunistic infections, but I imagine it would be the same for pathogenic infections as well:
https://www.sciencedirect.com/science/article/pii/B9780444632692000180

“Infections are common causes of morbidity and mortality in autoimmune diseases, and opportunistic infections are the tip of this problem, emerging as one main causes of morbidity in these patients...Use of immunosuppressors in the treatment of autoimmune diseases has increased opportunistic infections related to therapy, although disease itself and comorbilities can also be factors affecting susceptibility”.

 

1) Agreed with extreme caution in not seeking this drug outside of clinical trial and without close supervision of a physician knowledgeable with this particular drug.

2) With all chemotherapies, there is a chance of contracting other cancers such as leukemia or lymphomas, not just bladder cancer in the specific case of Cyclo.

3) We still need biomarkers and quantitative biological markers of improvement.

4) Once we understand the mechanism of illness, better drugs can be developed, hopefully with a better safety profile.

5) Now what?

 

5): Multicenter phase 3!

 

Multicenter phase 3 if you want to wait about 6+ years. The current study began in 2015 and was published in 2020. A phase 3 study is more complex, plus they have to secure funding. So maybe published in 2027 or 2028. This is not a great option if you have progressive MECFS.

 

Anyone see appendix G or G1? Thanks.

 

It take in average 17 years to put a drug on the market- this includes all trial phases, testing for efficacy and safety. These studies are necessary and should be done rigorously.

It’s difficult (and expensive) in the best of example to put a drug on the market. Consider level of understanding of the disease, investment of researchers, and overcoming barriers- there are many with ME.

 

Cyclophosphamide is already approved and on the market, so not 17 years.

 

You do a 40/40 Phase II trial placebo-controlled with actual objective aerobic testing, exclude anyone with disease course variation and you slam it through in a year.

Do it this paper's way and you can finesse natural disease course variation without a placebo and harness the placebo effect present in SF-36, which is even worse with intravenous.

 

Correct, already on the market, but indicated for other diseases, most of it being cancer.

You still have to test safety in the ME population, the ideal dosage, the regimen, the effectiveness, against a placebo, and insuring a representative patient population. Then you need to factor in that the time it takes to process each patient (including 6 month, 1 year, 18 months datapoint).

Some trials can be fast tracked, because of the short response time, for instance, testing the effectiveness of a new short acting pain killer.

It would take some time for ME experts to consider feasibility and willingness for a multi-center clinical trial. So i would not be surprise another 2 years elapsed just to find out whether such trial would go ahead. It’s not going to happen tomorrow.

edit to add: Cyclo is also a long existing drug, likely off-label. It means that funding for a trial is not likely to come from the manufacturer.

 

I never used cyclophosphamide alone in RA. In lupus improvement with cyclo is quicker. You do not expect a slow improvement with cyclophosphamide. The slow improvement with rituximab is due to the fact that it kills memory B cells but not plasma cells. Cyclo is indiscriminate. I don't know how to interpret a delay like this for cyclo.

 

I’m a little underwhelmed by this. Fatigue measure of 69.5 is not normal still and neither is just 5,589 steps. Can this be called remission? Improvement, yes, it seems so and perhaps that improvement is worth the risks with the drug but it doesn’t look like its fixed people to me, they are still ill, just not as ill.

And initially the non-responders also improved on these measures, albeit to a lesser degree. Was that a response to the drug as well, or will all these gains evaporate in a phase 3 trial?

 

They improvements could disappear in a phase 3 trial, but how does one explain the association between greater improvement and HLA alleles?

Is it possible that the treatment is no better than placebo, but the HLA alleles are protective and improve outcomes?

 

We've been down this road before with open label rituximab studies before the blinded RCT showed it was trending toward being worse than useless.

The results here are strongly suggestive of a spontaneous improvement / regression toward the mean / placebo response in patients who were probably on the trajectory of improving slightly anyway and now this improvement has been attributed to the drug because they happened to be on the drug while the improvement was happening. Humans have a natural tendency to attribute random events to specific causal factors which is why blinded studies are essential.

Their patients were mild to begin with (3,200 steps per day prior to treatment). The responders were doing better to begin with (3,622 steps prior to treatment) and the improvement in responders only increased their step count by ~2,000 steps which is well within the range of mild spontaneous improvement and wishful thinking encouraging people to push the boundaries of their existing energy envelope. I know many normal sedentary people who do only 3000-4000 steps per day. And when I had mild ME/CFS, I could do more steps than this yet was still feeling like death most of the time.

The SF-36 score in improved patients suggests that they were still maimed and functioning at the level of people with kidney or heart failure.

I hope that the unscrupulous doctors who prescribed rituximab off-label to (understandably desperate) patients despite constant warnings not to do so by the Norwegian researchers won't use this paper as justification for doing the same with cyclophosphamide considering its side effect profile.